We have previously shown that AZT-treatment of simian immunodeficiency virus (SIV)-infected newborn macaques resulted in reduced plasma viremia, enhanced antiviral immune responses, and delayed disease progression. However, AZT-treated animals had persistent cell-associated viremia and AZT-resistant SIVmac could be isolated. Thus, drugs that suppress virus replication more completely for long time periods are needed. Based on promising preliminary data, we are testing the long-term therapeutic and toxic effects of the cyclic nucleoside phosphonate derivative 9-(2-phosphonymethoxy-propyl)adenine (PMPA) in SIV-infected newborn macaques. Eight newborn macaques were inoculated orally with uncloned SIVmac251; four animals were used as untreated controls, while four animals were started at three weeks of age on prolonged PMPA treatment (30 mg/kg subcutaneously once per day). The untreated SIV-infected newborn macaques developed persistently high viremia and three of four developed rapidly fatal disease within 3 months. In contrast, long-term PMPA treatment, starting 3 weeks after virus inoculation, resulted in a rapid, pronounced and persistent reduction of viremia, and no toxic side-effects. Virus isolated from the four PMPA-treated SIV-infected infants after 3 to 4 months of therapy showed approximately 5-fold increased resistance to PMPA; this drug resistance was associated with the appearance of a single point mutation (substitution of lysine for arginine at amino acid 65) in the viral reverse transcriptase. Despite this low-level drug resistance, virus levels remain low (approximately 1 infected cell per million peripheral blood mononuclear cells) in three of the four treated animals. All four PMPA-treated animals have remained disease-free for more than 9 months. These results indicate that PMPA therapy can significantly reduce virus load and delay disease progression in SIV-infected rhesus neonates and is efficacious for long periods of time without harmful side-effects. *KEY* Pediatric simian AIDS, Oral SIV transmission, Antiretroviral drug resistance, 9-(2-phosphonylmethoxy-propyl)adenine